Field of the Invention
The invention generally relates to homogenous, synthetic, small molecules that selectively inhibit the growth of cancer stem cells, for example colorectal cancer stem cells, and prevent replacement or recurrence of the observed cancer.
Background of the Invention
The cancer stem-like cell (CSC) hypothesis has attracted a lot of attention as a unifying hypothesis that explains the shortcomings of current anti-cancer therapeutics and posits a paradigm-shifting direction for the discovery of potential, new anti-cancer agents (1,2). Primary and acquired resistances to cytotoxic therapies play a major role in disease recurrence in a majority of advanced epithelial malignancies including colorectal cancer. This phenomenon is thought to be the result of the extended survival of a small population of CSCs with the ability to self-renew and reconstitute the entire tumor (3). Additionally, the CSCs also possess the ability to invade and metastasize, which is more detrimental in a majority of cases. A new approach is critically needed to prevent disease recurrence arising from inability to destroy CSCs.
A therapeutic paradigm that is gaining momentum is targeting CSCs through either inhibition of CSC self-renewal or induction of differentiation, should be singularly effective in eradicating a tumor (4,5). Further, CSC targeting may display an added advantage of a ‘magic bullet’ because of the possibility of simultaneously treating several types of cancers arising from the mechanistic similarity expected at the CSC level.
Although attractive, targeting CSCs is intrinsically challenging. CSCs comprise only a small percent of the overall tumor cell population, which implies that high-throughput screening (HTS) approaches that utilize bulk cancer cells are likely to not identify CSC-specific agents. Gupta et al. have used epithelial-mesenchymal transition (EMT) in a breast cancer cell line to enhance the proportion of CSCs, which enabled application of HTS on a library of small molecules and extracts. The work resulted in the identification of salinomycin, but not paclitaxel (a known anticancer drug), as a preferential inhibitor of CSCs (6). Recent application of this technology has led to identification of three probes from the NIH Molecular Libraries Program as potent inhibitors of breast CSCs (7-11). While salinomycin is a polyketide synthase-derived natural product, probes ML239, ML243 and ML245 are chemically synthesizable, small hydrophobic molecules. The identification of only four molecules targeting CSC (and that to only breast CSC) in the past five years highlights the difficulty of identifying CSC-based therapeutics. For the CSC paradigm to translate into therapeutic success, a more fundamental and generalizable approach is needed.